SPOCK3

Summary

SPOCK3 (SPARC (osteonectin), cwcv and kazal like domains proteoglycan 3, HGNC:13565) is a protein-coding gene on chromosome 4q32.3, encoding Testican-3 (Q9BQ16). May participate in diverse steps of neurogenesis.

This gene encodes a member of a novel family of calcium-binding proteoglycan proteins that contain thyroglobulin type-1 and Kazal-like domains. The encoded protein and may play a role in adult T-cell leukemia by inhibiting the activity of membrane-type matrix metalloproteinases. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene.

Source: NCBI Gene 50859 — RefSeq curated summary.

At a glance

• GWAS associations: 11
• Clinical variants (ClinVar): 75 total — 2 pathogenic
• MANE Select transcript: NM_001040159

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:13565
Approved symbol	SPOCK3
Name	SPARC (osteonectin), cwcv and kazal like domains proteoglycan 3
Location	4q32.3
Locus type	gene with protein product
Status	Approved
Aliases	testican-3
Ensembl gene	ENSG00000196104
Ensembl biotype	protein_coding
OMIM	607989
Entrez	50859

Gene structure

Transcript identifiers

Ensembl transcripts: 31 — 22 protein_coding, 9 nonsense_mediated_decay

ENST00000357154, ENST00000357545, ENST00000421836, ENST00000502330, ENST00000502741, ENST00000502821, ENST00000504953, ENST00000505187, ENST00000506697, ENST00000506886, ENST00000507086, ENST00000507370, ENST00000509854, ENST00000510403, ENST00000510741, ENST00000511226, ENST00000511269, ENST00000511531, ENST00000511905, ENST00000512042, ENST00000512648, ENST00000512681, ENST00000515143, ENST00000515316, ENST00000535728, ENST00000541354, ENST00000874039, ENST00000874040, ENST00000874041, ENST00000874042, ENST00000943358

RefSeq mRNA: 10 — MANE Select: NM_001040159 NM_001040159, NM_001204352, NM_001204353, NM_001204354, NM_001204355, NM_001204356, NM_001204358, NM_001251967, NM_001430594, NM_016950

CCDS: CCDS34095, CCDS54817, CCDS56343, CCDS56344, CCDS56346, CCDS56347, CCDS58931, CCDS75207

Canonical transcript exons

ENST00000357545 — 11 exons

Exon	Start	End
ENSE00001433822	166733384	166735090
ENSE00002087127	167234450	167234494
ENSE00003516986	166889130	166889244
ENSE00003529531	167000349	167000463
ENSE00003537198	166792170	166792289
ENSE00003540423	166754508	166754729
ENSE00003578779	167062492	167062537
ENSE00003593635	166737467	166737604
ENSE00003600328	166912620	166912743
ENSE00003603796	167233985	167234173
ENSE00003659996	166741997	166742059

Expression profiles

Bgee: expression breadth ubiquitous, 213 present calls, max score 98.60.

FANTOM5 (CAGE): breadth broad, TPM avg 9.9281 / max 1031.2089, expressed in 373 samples.

FANTOM5 promoters (8 alternative TSS)

Promoter ID	TPM avg	Samples expressed
54748	5.9114	250
54750	1.9997	195
54749	0.9972	133
54751	0.3280	105
54745	0.2820	93
54744	0.2100	61
54747	0.1171	69
54746	0.0826	47

Top tissues by expression

285 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
lateral globus pallidus	UBERON:0002476	98.60	gold quality
globus pallidus	UBERON:0001875	98.55	gold quality
endothelial cell	CL:0000115	98.54	gold quality
medial globus pallidus	UBERON:0002477	98.54	gold quality
corpus callosum	UBERON:0002336	98.31	gold quality
substantia nigra pars reticulata	UBERON:0001966	98.30	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	98.18	gold quality
substantia nigra pars compacta	UBERON:0001965	98.06	gold quality
subthalamic nucleus	UBERON:0001906	98.01	gold quality
inferior vagus X ganglion	UBERON:0005363	97.96	gold quality
spinal cord	UBERON:0002240	97.34	gold quality
cauda epididymis	UBERON:0004360	97.26	gold quality
pons	UBERON:0000988	96.63	gold quality
lateral nuclear group of thalamus	UBERON:0002736	96.51	gold quality
superior vestibular nucleus	UBERON:0007227	96.39	gold quality
caudate nucleus	UBERON:0001873	95.96	gold quality
Brodmann (1909) area 23	UBERON:0013554	95.96	gold quality
putamen	UBERON:0001874	95.72	gold quality
Ammon’s horn	UBERON:0001954	95.37	gold quality
nucleus accumbens	UBERON:0001882	95.15	gold quality
primary visual cortex	UBERON:0002436	94.73	gold quality
midbrain	UBERON:0001891	94.71	gold quality
substantia nigra	UBERON:0002038	94.58	gold quality
ventral tegmental area	UBERON:0002691	94.56	gold quality
prefrontal cortex	UBERON:0000451	94.33	gold quality
amygdala	UBERON:0001876	94.30	gold quality
hypothalamus	UBERON:0001898	94.04	gold quality
occipital lobe	UBERON:0002021	93.88	gold quality
dorsal plus ventral thalamus	UBERON:0001897	93.28	gold quality
temporal lobe	UBERON:0001871	93.14	gold quality

Single-cell (SCXA)

Detected in 13 experiment(s), a significant marker in 10.

Experiment	Marker?	Max mean expression
E-CURD-6	yes	101.82
E-HCAD-35	yes	96.24
E-HCAD-25	yes	54.78
E-MTAB-5061	yes	26.31
E-GEOD-81608	yes	21.26
E-GEOD-84465	yes	13.17
E-GEOD-83139	yes	8.56
E-ENAD-27	yes	8.11
E-MTAB-9388	yes	7.01
E-ANND-3	yes	5.47
E-HCAD-5	no	413.61
E-MTAB-7303	no	212.18
E-ENAD-17	no	35.93

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

182 targeting SPOCK3, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-30A-5P	100.00	76.31	3233
HSA-MIR-30B-5P	100.00	76.29	3248
HSA-MIR-30C-5P	100.00	76.29	3248
HSA-MIR-30D-5P	100.00	76.32	3233
HSA-MIR-30E-5P	100.00	76.32	3242
HSA-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-574-5P	100.00	66.01	989
HSA-MIR-3924	100.00	72.09	2394
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-4803	99.98	71.99	3117
HSA-MIR-4789-5P	99.98	70.76	2721
HSA-LET-7F-2-3P	99.98	70.98	2588
HSA-MIR-1185-1-3P	99.98	71.04	2593
HSA-MIR-1185-2-3P	99.98	71.04	2593
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-548N	99.98	71.94	4170

Literature-anchored findings (GeneRIF, showing 6)

• High expression of testican 3 is associated with adult T-cell leukemia. (PMID:19144404)
• The results of this study suggest that SPOCK3 may modify the genetic risk for Attention-deficit/hyperactivity disorder and personality disorders (PMID:24292267)
• associations, near SPOCK3 were identified and other putative modulators of memory performance were revealed by a (PMID:25648963)
• Mechanism of prognostic marker SPOCK3 affecting malignant progression of prostate cancer and construction of prognostic model. (PMID:37563543)
• Proteins linking APOE varepsilon4 with Alzheimer’s disease. (PMID:38856164)
• SPOCK: Master regulator of malignant tumors (Review). (PMID:39392048)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	spock3	ENSDARG00000070266
mus_musculus	Spock3	ENSMUSG00000054162
rattus_norvegicus	Spock3	ENSRNOG00000029903
drosophila_melanogaster	Cow	FBGN0039054
caenorhabditis_elegans		WBGENE00016918

Paralogs (3): SPOCK2 (ENSG00000107742), SPOCK1 (ENSG00000152377), KIAA1210 (ENSG00000250423)

Protein

Protein identifiers

Testican-3 — Q9BQ16 (reviewed: Q9BQ16)

Alternative names: SPARC/osteonectin, CWCV, and Kazal-like domains proteoglycan 3

All UniProt accessions (12): Q9BQ16, A0A0A0MTJ2, B4DG04, E7EMP8, E7ENM6, E7ENT7, E7ENY3, E7EQ24, E7ESN1, E7EVH4, H0YA19, Q4W5S3

UniProt curated annotations — full annotation on UniProt →

Function. May participate in diverse steps of neurogenesis. Inhibits the processing of pro-matrix metalloproteinase 2 (MMP-2) by MT1-MMP and MT3-MMP. May interfere with tumor invasion.

Subcellular location. Secreted. Extracellular space. Extracellular matrix.

Tissue specificity. Expressed in brain.

Post-translational modifications. Contains chondroitin sulfate and heparan sulfate O-linked oligosaccharides.

Isoforms (9)

UniProt ID	Names	Canonical?
Q9BQ16-3	3	yes
Q9BQ16-1	1
Q9BQ16-2	2, N-tes
Q9BQ16-4	4
Q9BQ16-5	5
Q9BQ16-6	6
Q9BQ16-7	7
Q9BQ16-8	8
Q9BQ16-9	9

RefSeq proteins (10): NP_001035249, NP_001191281, NP_001191282, NP_001191283, NP_001191284, NP_001191285, NP_001191287, NP_001238896, NP_001417523, NP_058646 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000716	Thyroglobulin_1	Domain
IPR002350	Kazal_dom	Domain
IPR011992	EF-hand-dom_pair	Homologous_superfamily
IPR019577	SPARC/Testican_Ca-bd-dom	Domain
IPR036058	Kazal_dom_sf	Homologous_superfamily
IPR036857	Thyroglobulin_1_sf	Homologous_superfamily

Pfam: PF00086, PF07648, PF10591

UniProt features (28 total): splice variant 9, disulfide bond 8, domain 2, sequence conflict 2, glycosylation site 2, signal peptide 1, chain 1, sequence variant 1, region of interest 1, compositionally biased region 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9BQ16-F1	66.57	0.05

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Disulfide bonds (8): 139–169, 142–162, 151–183, 317–341, 352–359, 361–380, 90–101, 95–111

Glycosylation sites (2): 387, 392

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-1592389	Activation of Matrix Metalloproteinases
R-HSA-1474228	Degradation of the extracellular matrix
R-HSA-1474244	Extracellular matrix organization

MSigDB gene sets: 190 (showing top): GOBP_NEGATIVE_REGULATION_OF_PROTEOLYSIS, BENPORATH_ES_WITH_H3K27ME3, chr4q32, GOBP_NEGATIVE_REGULATION_OF_HYDROLASE_ACTIVITY, ASTON_MAJOR_DEPRESSIVE_DISORDER_DN, CHANDRAN_METASTASIS_DN, GOBP_REGULATION_OF_HYDROLASE_ACTIVITY, MCLACHLAN_DENTAL_CARIES_DN, SHETH_LIVER_CANCER_VS_TXNIP_LOSS_PAM5, GOBP_REGULATION_OF_PEPTIDASE_ACTIVITY, GOBP_NEGATIVE_REGULATION_OF_MOLECULAR_FUNCTION, GOBP_NEGATIVE_REGULATION_OF_CATALYTIC_ACTIVITY, GOBP_NEGATIVE_REGULATION_OF_PROTEIN_METABOLIC_PROCESS, GOMF_GLYCOSAMINOGLYCAN_BINDING, GOBP_REGULATION_OF_CELL_SUBSTRATE_ADHESION

GO Biological Process (2): negative regulation of endopeptidase activity (GO:0010951), negative regulation of cell motility (GO:2000146)

GO Molecular Function (8): calcium ion binding (GO:0005509), collagen binding (GO:0005518), glycosaminoglycan binding (GO:0005539), metalloendopeptidase inhibitor activity (GO:0008191), extracellular matrix binding (GO:0050840), enzyme inhibitor activity (GO:0004857), protein binding (GO:0005515), peptidase inhibitor activity (GO:0030414)

GO Cellular Component (3): obsolete extracellular space (GO:0005615), extracellular matrix (GO:0031012), extracellular region (GO:0005576)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Degradation of the extracellular matrix	1
Extracellular matrix organization	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
binding	2
endopeptidase activity	1
negative regulation of peptidase activity	1
regulation of endopeptidase activity	1
negative regulation of locomotion	1
negative regulation of cellular process	1
cell motility	1
regulation of cell motility	1
metal ion binding	1
protein-containing complex binding	1
carbohydrate derivative binding	1
metalloendopeptidase activity	1
endopeptidase inhibitor activity	1
catalytic activity	1
enzyme regulator activity	1
molecular function inhibitor activity	1
enzyme inhibitor activity	1
peptidase activity	1
peptidase regulator activity	1
external encapsulating structure	1
cellular anatomical structure	1

Protein interactions and networks

STRING

1382 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SPOCK3	MMP16	P51512	843
SPOCK3	MMP14	P50281	668
SPOCK3	FST	P19883	630
SPOCK3	MMP2	P08253	511
SPOCK3	MMP1	P03956	485
SPOCK3	RIC8B	Q9NVN3	454
SPOCK3	SMOC1	Q9H4F8	433
SPOCK3	CCDC14	Q49A88	404
SPOCK3	MRPS18C	Q9Y3D5	398
SPOCK3	ERBB2	P04626	368
SPOCK3	SMOC2	Q9H3U7	365
SPOCK3	ANXA10	Q9UJ72	353
SPOCK3	KCNIP4	Q6PIL6	311
SPOCK3	SCP2D1	Q9UJQ7	300
SPOCK3	SH2D4A	Q9H788	286

IntAct

5 interactions, top by confidence:

A	B	Type	Score
SPOCK3	CREB3	psi-mi:“MI:0915”(physical association)	0.370
SPOCK3		psi-mi:“MI:0915”(physical association)	0.370
TNIP1	COCH	psi-mi:“MI:0914”(association)	0.350
Gpr158	AGRN	psi-mi:“MI:0914”(association)	0.350

BioGRID (9): SPOCK3 (Affinity Capture-Western), SPOCK3 (Two-hybrid), SPOCK3 (Affinity Capture-Western), SPOCK2 (Affinity Capture-Western), SPOCK3 (Affinity Capture-MS), MMP3 (Affinity Capture-Western), MMP14 (Affinity Capture-Western), SPOCK3 (Positive Genetic), SPOCK3 (Proximity Label-MS)

ESM2 similar proteins: A2RUV9, F8W3R9, O18738, O43278, O54858, O88393, O97827, P00734, P00735, P0C5J5, P12259, P18292, P26342, P35054, P51511, Q08629, Q08E66, Q09101, Q14118, Q24567, Q24568, Q28685, Q29243, Q5R537, Q5RD69, Q62165, Q62288, Q640N1, Q66K79, Q701R2, Q7TQN3, Q80TS3, Q8BKV0, Q8IUX7, Q8N436, Q8R4V4, Q8TEU8, Q91ZV2, Q91ZV3, Q92563

Diamond homologs: A0A1D0C023, A2ARV4, B3EWY9, B3NBB6, B4HVU2, B4PD96, B5DFC9, F1RRV3, O08523, O08710, O42182, O73775, O75095, O75197, O75443, O75581, O77469, O88322, O88572, P01130, P01131, P01266, P01267, P04233, P04441, P06882, P07522, P08460, P10247, P10493, P14543, P20063, P23142, P27590, P31226, P35442, P35443, P35444, P35445, P48960

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

75 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	2
Likely pathogenic	0
Uncertain significance	61
Likely benign	3
Benign	3

Top pathogenic / likely-pathogenic (2)

Variant ID	HGVS	Classification
149581	GRCh38/hg38 4q28.1-35.1(chr4:125432943-185761887)x3	Pathogenic
1711165	GRCh37/hg19 4q32.3(chr4:166940253-167778165)x3	Pathogenic

SpliceAI

3789 predictions. Top by Δscore:

Variant	Effect	Δscore
4:166735087:ATAGC:A	acceptor_loss	1.0000
4:166735090:GCTTA:G	acceptor_loss	1.0000
4:166735091:C:CC	acceptor_gain	1.0000
4:166735091:CTTA:C	acceptor_loss	1.0000
4:166735092:T:C	acceptor_gain	1.0000
4:166735092:T:TC	acceptor_gain	1.0000
4:166737461:CCTTA:C	donor_loss	1.0000
4:166737462:CTTAC:C	donor_loss	1.0000
4:166737463:TTACC:T	donor_loss	1.0000
4:166737465:A:AC	donor_gain	1.0000
4:166737466:C:CC	donor_gain	1.0000
4:166737466:CCA:C	donor_gain	1.0000
4:166737600:CTGTC:C	acceptor_gain	1.0000
4:166742060:C:CC	acceptor_gain	1.0000
4:166754725:GAATC:G	acceptor_gain	1.0000
4:166754726:AATC:A	acceptor_gain	1.0000
4:166754727:ATC:A	acceptor_gain	1.0000
4:166754727:ATCC:A	acceptor_loss	1.0000
4:166754727:ATCCT:A	acceptor_gain	1.0000
4:166754728:TC:T	acceptor_gain	1.0000
4:166754729:CC:C	acceptor_gain	1.0000
4:166754730:C:CC	acceptor_gain	1.0000
4:166754730:C:T	acceptor_gain	1.0000
4:166754731:T:G	acceptor_loss	1.0000
4:166754737:C:CT	acceptor_gain	1.0000
4:166754738:A:T	acceptor_gain	1.0000
4:166792168:A:AC	donor_gain	1.0000
4:166792169:C:CC	donor_gain	1.0000
4:166792169:CTG:C	donor_gain	1.0000
4:166889124:ACTT:A	donor_loss	1.0000

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000005138 (4:167022805 G>A), RS1000007019 (4:167061261 C>A), RS1000007830 (4:167077628 C>G), RS1000019649 (4:167110209 C>T), RS1000021581 (4:166754056 G>A,C,T), RS10000273 (4:166745612 C>A,T), RS1000035769 (4:166936925 C>T), RS10000380 (4:167051485 G>A), RS1000039984 (4:167103093 C>T), RS1000051547 (4:167018562 G>A,T), RS10000535 (4:166977166 A>G), RS1000058444 (4:167160347 C>A,T), RS1000064278 (4:167016377 A>C), RS1000064845 (4:167144996 C>T), RS1000065701 (4:166842849 C>T)

Disease associations

OMIM: gene MIM:607989 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

11 associations (top):

Study	Trait	p-value
GCST001534_5	Immune reponse to smallpox (secreted IL-10)	3.000000e-11
GCST001762_627	Obesity-related traits	3.000000e-06
GCST001762_838	Obesity-related traits	8.000000e-07
GCST002701_25	Verbal declarative memory	3.000000e-08
GCST004823_5	Cognitive function	4.000000e-06
GCST006585_1886	Blood protein levels	5.000000e-96
GCST008152_113	Weight	4.000000e-06
GCST009190_6	Medial orbital frontal cortex volume	4.000000e-06
GCST010396_210	Gut microbiota (bacterial taxa, hurdle binary method)	4.000000e-06
GCST010396_285	Gut microbiota (bacterial taxa, hurdle binary method)	2.000000e-08
GCST012439_1	Total antioxidant status in non-alcoholic fatty liver disease x mastiha supplementation interaction	1.000000e-08

EFO canonical traits (11, from GWAS)

EFO ID	Trait name
EFO:0004645	response to vaccine
EFO:0004873	cytokine measurement
EFO:0004611	low density lipoprotein cholesterol measurement
EFO:0004574	total cholesterol measurement
EFO:0004874	memory performance
EFO:0006805	word list delayed recall measurement
EFO:0008354	cognitive function measurement
EFO:0004338	body weight
EFO:0007874	gut microbiome measurement
EFO:0005119	antioxidant measurement
EFO:0600067	mastiha supplement exposure measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

29 total (human), top 29 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression, affects expression	6
Benzo(a)pyrene	decreases expression, increases methylation	3
Aflatoxin B1	decreases expression	3
lasiocarpine	decreases expression	2
methyleugenol	decreases expression	2
trichostatin A	increases expression	2
N-Nitrosopyrrolidine	decreases expression	2
Phenylmercuric Acetate	affects cotreatment, increases expression	2
Tobacco Smoke Pollution	decreases expression	2
aristolochic acid I	decreases expression	1
ethyl-p-hydroxybenzoate	increases expression	1
sodium arsenite	affects methylation	1
CGP 52608	affects binding, increases reaction	1
3-nitrobenzanthrone	decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
dorsomorphin	affects cotreatment, increases expression	1
Fulvestrant	decreases methylation	1
Air Pollutants	decreases expression, increases abundance	1
Estradiol	increases expression	1
Folic Acid	increases expression	1
Smoke	decreases expression, increases abundance	1
Tetrachlorodibenzodioxin	increases expression	1
Tretinoin	increases expression	1
1-Methyl-4-phenylpyridinium	decreases expression	1
Antirheumatic Agents	increases expression	1
Okadaic Acid	decreases expression	1
Copper Sulfate	increases expression	1
Raloxifene Hydrochloride	increases expression	1
Particulate Matter	decreases expression	1

Clinical trials (associated diseases)

0 trials via MONDO — disease-level, not drug-specific.